Association of CaMK2A and MeCP2 signaling pathways with cognitive ability in adolescents

Li-Ching Lee,Hsing-Ying Huang,Ting-Kuang Yeh,Chun-Yen Chang,Ming-Tsan Su,Ying-Chun Cho

doi:10.1186/s13041-021-00858-8

Li-Ching Lee, Hsing-Ying Huang + Show 4 more

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https://doi.org/10.1186/s13041-021-00858-8

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Journal: Molecular brain	Publication Date: Oct 4, 2021
Citations: 4	License type: open-access

Affiliation: National Taiwan Normal University

Abstract

The glutamatergic signaling pathway is involved in molecular learning and human cognitive ability. Specific single variants (SNVs, formerly single-nucleotide polymorphisms) in the genes encoding N-methyl-d-aspartate receptor subunits have been associated with neuropsychiatric disorders by altering glutamate transmission. However, these variants associated with cognition and mental activity have rarely been explored in healthy adolescents. In this study, we screened for SNVs in the glutamatergic signaling pathway to identify genetic variants associated with cognitive ability. We found that SNVs in the subunits of ionotropic glutamate receptors, including GRIA1, GRIN1, GRIN2B, GRIN2C, GRIN3A, GRIN3B, and calcium/calmodulin-dependent protein kinase IIα (CaMK2A) are associated with cognitive function. Plasma CaMK2A level was correlated positively with the cognitive ability of Taiwanese senior high school students. We demonstrated that elevating CaMK2A increased its autophosphorylation at T286 and increased the expression of its downstream targets, including GluA1 and phosphor- GluA1 in vivo. Additionally, methyl-CpG binding protein 2 (MeCP2), a downstream target of CaMK2A, was found to activate the expression of CaMK2A, suggesting that MeCP2 and CaMK2A can form a positive feedback loop. In summary, two members of the glutamatergic signaling pathway, CaMK2A and MeCP2, are implicated in the cognitive ability of adolescents; thus, altering the expression of CaMK2A may affect cognitive ability in youth.

Highlights

N-methyl-d-aspartate receptors (NMDARs) are ionotropic glutamate receptors crucial for neuronal communication, which plays a central role in learning, memory, and synaptic development
We discovered that single-nucleotide variants (SNVs) in Calcium/ calmodulin-dependent protein kinase IIα (CaMK2A) and the subunits of ionotropic glutamate receptors, including GRIN1, GRIN2B, GRIN2C, GRIN3A, GRIN3B, GRIA1, and GRID1, are associated with student cognitive function
We found that SNVs in genes encoding NMDAR subunits were associated with academic performance and cognitive ability (Table 1)

Summary

Introduction

N-methyl-d-aspartate receptors (NMDARs) are ionotropic glutamate receptors crucial for neuronal communication, which plays a central role in learning, memory, and synaptic development. Synaptic proteins play a crucial role in synaptic activity and dendritic spine morphogenesis, and variations in synaptic proteins lead to cognitive deficits [13]. Of all the genes involved in cognitive function, members of the glutamatergic signaling pathway are the most interesting [15]. Glutamate is a major excitatory neurotransmitter involved in learning and memory, long-term potentiation (LTP), and synaptic plasticity [16]. Glutamate binds to and activates ionotropic receptors (e.g., NMDA) and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs) and mediates Ca2+ transport, activating intracellular signaling cascades to alter synaptic efficacy and induce LTP [17]

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